An examination of the relationship between hotspots and recombination associated with chromosome 21 nondisjunction

Abstract

Trisomy 21, resulting in Down Syndrome (DS), is the most common autosomal trisomy among live-born infants and is caused mainly by nondisjunction of chromosome 21 within oocytes. Risk factors for nondisjunction depend on the parental origin and type of meiotic error. For errors in the oocyte, increased maternal age and altered patterns of recombination are highly associated with nondisjunction. Studies of normal meiotic events in humans have shown that recombination clusters in regions referred to as hotspots. In addition, GC content, CpG fraction, Poly(A)/Poly(T) fraction and gene density have been found to be significant predictors of the placement of sex-averaged recombination in the human genome. These observations led us to ask whether the altered patterns of recombination associated with maternal nondisjunction of chromosome 21 could be explained by differences in the relationship between recombination placement and recombination-related genomic features (i.e., GC content, CpG fraction, Poly(A)/Poly(T) fraction or gene density) on 21q or differential hot-spot usage along the nondisjoined chromosome 21. We found several significant associations between our genomic features of interest and recombination, interestingly, these results were not consistent among recombination types (single and double proximal or distal events). We also found statistically significant relationships between the frequency of hotspots and the distribution of recombination along nondisjoined chromosomes. Collectively, these findings suggest that factors that affect the accessibility of a specific chromosome region to recombination may be altered in at least a proportion of oocytes with MI and MII errors.

Figure 1. The distribution of single recombination events across the long arm of 21q by population.

21q was divided into 66 500

Figure 2. The distribution of the proximal recombinant of a double recombinant event across the long arm of 21q by population.

21q was divided into 66 500

Figure 3. The distribution of the distal recombinant of a double recombinant event across the long arm of 21q by population.

21q was divided into 66 500

Figure 4. Comparison of the relationship between hotspot usage between MI and MII cases and Controls.

Figure 4A and 4B represent MI and MII cases respectively with only one recombinant event on 21q. The solid line represents the relationship between the number of hotspots per bin and the proportion of recombination per bin along normally segregating chromosomes 21. The dotted line represents the relationship between the number of hotspots per bin and the proportion of recombination per bin along chromosomes 21 from MI errors (figure 4A) and MII errors (figure 4B).

Figure 5. Comparison of slopes between MI or MII errors and controls for the proximal recombinant of double recombinant events.

Figures 5A and 5B represent data from the proximal recombinant event of chromosomes displaying two recombinant events on 21q. The solid line represents the relationship between the number of hotspots per bin and the proportion of recombination per bin along normally segregating chromosomes 21. The dotted line represents the relationship between the number of hotspots per bin and the proportion of recombination per bin along chromosomes 21 from MI errors (figure 5A) and MII errors (figure 5B).

Figure 6. Comparison of slopes between MI or MII errors and controls for the distal recombinant of double recombinant events.

Figures 6A and 6B represent data from the distal recombinant event of chromosomes displaying two recombinant events on 21q. The solid line represents the relationship between the number of hotspots per bin and the proportion of recombination per bin along normally segregating chromosomes 21. The dotted line represents the relationship between the number of hotspots per bin and the proportion of recombination per bin along chromosomes 21 from MI errors (figure 6A) and MII errors (figure 6B).